Cystic fibrosis is a devastating, chronic, progressive, and frequently fatal genetic disease that is particularly manifest in the lungs. The major cause is an abnormality in ion transport across cell membranes by the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is the dominant chloride ion transporter in several epithelial tissues. Two adapter proteins-Na+/H+ exchanger regulator factor (NHERF) and ezrin-regulate the cell surface concentrations of CFTR, organize the macromolecular interactions of CFTR with a network of signaling proteins for efficient transduction, and ultimately control the strength of chloride ion transport. The goal of this research is to determine the molecular mechanisms by which adapter proteins work in coordination to regulate the macromolecular assembly of CFTR. The central hypothesis to be tested is that NHERF is a signal transducer whose specific intra-molecular interactions, which are modulated by ezrin, control the ability of NHERF to assemble CFTR. By studying the architecture, energetics, and dynamics of the formation of CFTR macromolecular complexes assembled by multivalent adapter proteins, this research will provide a quantitative analysis of the molecular mechanisms by which adapter proteins interact to assembly CFTR channels. A molecular understanding of the macromolecular interactions with CFTR is an essential element for developing a therapeutic strategy for the cure of cystic fibrosis.